Quorum sensing is a type of bacterial cell-to-cell communication, and it is achieved through the production, release and detection of small signaling molecules called autoinducers (AIs). There are two major types of AIs, AI-1 and AI-2. AI-1 includes acylated homoserine lactones and modified peptides, which serve as intra-species signaling molecules. AI-2 is a furanosyl borate diester, a byproduct in the activated methyl cycle of bacteria. AI-2 is an interspecies signaling molecule, which is shared by both gram-negative and gram-positive bacteria. LuxS, S-Ribosylhomocysteinase, is a key enzyme in the biosynthesis of AI-2. The LuxS-dependent quorum sensing systems regulate a diverse array of physiological and pathological activities in bacteria, such as virulence factor expression and biofilm formation. LuxS proteins are well conserved, and its orthologs have been found in over 55 bacterial species, but absent in human. Due to these features, LuxS can be a potential molecular target for developing a novel class of antibiotic agents. Human oral microbial-plaques are biofilms composed of numerous genetically distinct types of bacteria that live in close juxtaposition on host surfaces. Growth as biofilms is essential for oral bacteria to adapt and thrive in oral flora and cause oral infections. Numerous studies have shown that the LuxS- dependent QS systems play very important roles in many oral bacteria in terms of biofilm formation, and production of virulence factors. Thus, LuxS can be a potential target for developing therapeutic agents to prevent or treat periodontal diseases. The goal of this application is to develop LuxS-based therapeutic compounds that specifically inhibit the biofilm formation of pathogenic oral bacteria such as Pg. To achieve this goal, the current application focuses on the following specific aims: (1) To elucidate the biochemical and structural features of LuxS proteins of Sg and Pg; (2) To design and screen specific compounds that inhibit the activity of Pg LuxS in vitro; and (3) To screen the compounds that specifically inhibit the biofilm formation of Pg but not Sg. The accomplishment of these studies will not only lead to a better understanding the biochemical and structural features of LuxS proteins from oral bacteria, but could also provide new means of prevention and treatment of periodontal diseases. PUBLIC HEALTH RELEVANCE: Periodontal infections are caused by a group of oral bacteria that grow as biofilms (plaque) in oral flora. Growth as biofilms is essential for oral bacteria to adapt and thrive in oral flora and cause the infections. The goal of this application is to develop inhibitors that are able to inhibit the biofilm formation of oral bacteria.